The invention relates to the field of cell type-specific gene expression.
Gene therapy holds promise for treating a wide variety of human metabolic diseases that are incurable or difficult to treat by more conventional procedures (reviewed in Mulligan, Science 260:926-932, 1993; Leiden, N. Eng. J. Med. 333:871-873, 1995). Gene therapy for disorders in the nervous system are particularly challenging because of the postmitotic state of most neurons, the complex nature of many brain diseases, extremely heterogeneous structure and function of different subtypes of neurons, and poorly understood control mechanisms of most brain-specific genes.
Parkinson's disease (PD), one of the most common neurodegenerative diseases in the world, is caused by specific neuronal loss of midbrain dopaminergic (DA) neurons. Gene therapy approach has great potential for treatment of PD (Costantini et al., Hum. Gene Ther. 10: 2481-2494, 1999; Constantini et al., Gene Ther. 7:93-109, 2000). For example, recent work by Kordower et al. (Science 290:767-773, 2000) demonstrated that lentiviral delivery of glial cell line-derived neurotrophic factor (GDNF) reversed functional deficits and completely prevented nigrostriatal degeneration in MPTP-treated monkey models of PD.
Based in part on the promise demonstrated the experiments such as the one described above, efficient promoter systems that can direct high level and long-term expression of therapeutic genes in a cell type-specific manner are in great need. Currently, most gene therapy procedures employ viral promoter systems such as CMV, RSV, and HSV IE promoters and have resulted in transient, high-level expression in most cell types. While transgene expression can be maintained stable at high-level under cell culture conditions, it rapidly diminishes in vivo following direct gene transfer or implantation of modified cells into target areas (During et al., Science 266:1399-1403, 1994; Palmer et al., Proc. Natl. Acad. Sci. USA 88:1330-1334, 1991). Furthermore, these viral promoters do not provide cell-type specific and controllable transgene expression. Thus it is desirable to use expression constructs that are capable of directing gene expression in differentiated neuronal cells in vivo, preferably in a cell type-specific manner.
Several studies have shown that two transcription factors, Nurr1 and Ptx3, are required for proper development and phenotypic specification of dopaminergic neurons (Smidt et al., Proc. Natl. Acad. Sci. USA 94:13305-13310, 1997; Zetterstrom et al., Science 276:248-250, 1997; Castillo et al., Mol. Cell Neurosci. 11:36-46, 1998; Saucedo-Cardenas et al., Proc. Natl. Acad. Sci. USA 95:4013-4018, 1998). Moreover, these transcription factors are selectively expressed in midbrain dopaminergic neurons.